HIV-associated neurocognitive disorder (HAND) is a major problem even in ART-treated people, and increasing in prevalence as people live longer on therapy. HAND results from chronic inflammation driven largely by activated monocyte/macrophage (M/M) lineage cells. An expansion of CD16+/CD163+ monocytes occurs in blood that is thought to invade the CNS (and may also carry virus into the brain). In the brain the accumulation of activated and/or infected M/M releases cytokines, small molecules or viral proteins that injure neurons, as well as chemokines such as MCP-1 that recruit additional M/M. Recent data indicate that despite antiretroviral suppression, there is persistence of both neuroinflammation and chronic systemic immune activation, driven largely by microbial translocation from a damaged gut barrier as well as residual viral expression. Persistent M/M activation is thus a critical target for adjunctive therapy to treat or prevent HAND. Statins are cholesterol lowering agents widely used to treat or prevent atherosclerosis. By blocking HMG-coA reductase, statins also prevent isoprenylation of intracellular signaling molecules, resulting in immunomodulatory activity believed also to contribute to clinical benefit. Activated M/M are principal inflammatory cells in atherosclerosis and important targets of statin immunomodulation. M/M activation in HAND has several striking parallels to that in atherosclerosis, and work by several groups in vitro and in vivo, as well as our preliminary data in vitro, show that statins downregulate M/M activation patterns implicated in HAND pathogenesis, including LPS-induced CD16 & CD163 upregulation, migration to MCP- 1, and MCP-1 production by M/M as well as astrocytes. We hypothesize that statins will suppress residual M/M activation associated with and mechanistically involved in HAND in ART- treated infected individuals and as such will be valuable adjuncts for prevention & treatment of neurocognitive disorders. In this project we will (1) Determine how statins modulate monocyte activation, intracellular signaling pathways and functions implicated in the pathogenesis of HAND in vitro; (2) Define the effect of atorvastatin on monocyte activation in HIV-infected/ART- treated subjects in a double-blind placebo- controlled crossover study; (3) Define gene expression patterns of residual monocyte activation in ART- treated subjects and modulation by statins, and; (4) Assess statin effects on CNS immune activation markers and neurocognitive function in ART-treated subjects. PUBLIC HEALTH RELEVANCE: Activation and inflammation involving monocyte/macrophage cells are a key component driving cognitive and neurological deficits in people with HIV infection, and these neurocognitive complications persist even if virus replication is suppressed by antiretroviral treatment. Statins are drugs widely used to treat atherosclerosis, and evidence suggests that part of their beneficial effect in that disease is through down-regulating monocyte/macrophage activation and inflammation. We will test if statins down-regulate monocyte/macrophage activation in HIV- infected people on antiretroviral therapy, and define the mechanisms behind this effect.